Epidemiological and clinical characteristics of respiratory syncytial virus and influenza infections in hospitalized children before and during the COVID‐19 pandemic in Central China

Abstract Background Globally, the epidemiology of non‐SARS‐CoV‐2 respiratory viruses like respiratory syncytial virus (RSV) and influenza virus was remarkably influenced by the implementation of non‐pharmacological interventions (NPIs) during the COVID‐19 pandemic. Our study explored the epidemiological and clinical characteristics of pediatric patients hospitalized with RSV or influenza infection before and during the pandemic after relaxation of NPIs in central China. Methods This hospital‐based prospective case‐series study screened pediatric inpatients (age ≤ 14 years) enrolled with acute respiratory infections (ARI) for RSV or influenza infection from 2018 to 2021. The changes in positivity rates of viral detection, epidemiological, and clinical characteristics were analyzed and compared. Results Median ages of all eligible ARI patients from 2018–2019 were younger than those from 2020–2021, so were ages of cases infected with RSV or influenza (RSV: 4.2 months vs. 7.2 months; influenza: 27.3 months vs. 37.0 months). Where the positivity rate for influenza was considerably decreased in 2020–2021 (1.4%, 27/1964) as compared with 2018–2019 (2.9%, 94/3275, P < 0.05), it was increased for RSV (11.4% [372/3275] vs. 13.3% [262/1964], P < 0.05) in the same period. The number of severe cases for both RSV and influenza infection were also decreased in 2020–2021 compared with 2018–2019. Conclusions The implemented NPIs have had varied impacts on common respiratory viruses. A more effective prevention strategy for RSV infections in childhood is needed.


| INTRODUCTION
Since December 2019, the world has been experiencing coronavirus disease 2019 (COVID- 19) pandemic. In China, the nationwide implemented non-pharmaceutical interventions (NPIs) were relaxed in April 2020 when the transmission of COVID-19 was under control. 1 These huge public health interventions which caused broad-spectrum changes in human behavior also affected the activity of other seasonal respiratory viruses such as respiratory syncytial virus (RSV) and influenza virus, as they share similar routes of transmission as severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Acute respiratory infections (ARI) especially viral lower respiratory tract infections, such as pneumonia and bronchiolitis caused by influenza and RSV are the leading causes of morbidity and mortality in children younger than 5 years. 2 After implementation of NPIs, a remarkable reduction in the circulation of influenza was commonly observed in almost all temperate zones and some tropical areas of the world. 3,4 However, this changed activity pattern of these viruses was not synchronous and varied from place to place. For example, in the winter of 2020, a low transmission of RSV and a delayed inter-seasonal resurgence was observed in Australia, Europe, and America. [5][6][7][8][9] There were several hospital-based studies from eastern and southern provinces of mainland China, which noted a high activity of RSV with a typical epidemic season. [10][11][12] However, no such studies are available, which covered the epidemiological and clinical information of patients from central China.
In this study, we aimed to report the impact of COVID-19 NPIs on the epidemiology and clinical characteristics of RSV and influenza infections in hospitalized pediatric patients from central China. Based on this prospective case-series study, multiple comparisons were made between these infections before and during the pandemic. The study was conducted on the largest campus (East Campus) of Henan Children's Hospital where three-fourths of all the inpatients were admitted. Participants were enrolled in three wards: general emergency ward, infant ward, and pediatric intensive care unit (PICU) as per the severity of illness. The PICU and general emergency ward admitted children aged 6 months to 14 years old, and infants (28 days to 6 months) were admitted to the infant ward.
All inpatients aged 14 years or less were screened for ARI. The inclusion criteria for an ARI patient needed: (i) admission to hospital with new illness onset of suspected ARI within 7 days for patients aged >3 months and an onset within 10 days for infants aged ≤3 months; (ii) manifestation of at least one of respiratory symptoms including cough, sore throat, rhinorrhea, and congestion of the nasal mucosa or pharynx; (iii) development of acute fever with an axillary temperature measured ≥37.5 C for patients aged >3 months. The date of illness onset was defined as the day when the symptom was first noticed. Pre-term birth: Babies are born alive before 37 weeks of pregnancy are completed.

| Sample collection and laboratory test
The enrolled ARI patients were approached for collection of respiratory specimens (throat swabs) within 24 h of hospitalization and then tested within 48 h for RSV and influenza infection by real timepolymerase chain reaction (RT-PCR). Methods for influenza and RSV detection are detailed in Supporting Information.

| Data collection
Demographics, medical history, underlying conditions such as preterm birth, and clinical information (including clinical manifestations, laboratory findings, chest radiography, and treatment) were extracted from electronic medical records of the hospital. The extracted data were recorded using a standardized data dictionary and REDCap system (Research Electronic Data Capture, Vanderbilt University, Nashville, Tennessee, USA) or EpiData v3.1. The data were checked for completeness and accuracy by the investigators. Information on birth weight and feeding patterns in the first year of life was also recorded if available.

| Statistical analysis
Continuous variables were described with medians and interquartile ranges (IQR) and categorical variables were described with frequencies and percentages. Comparisons of RSV or influenza infection characteristics were made using chi-square test. In case of limited data availability, Fisher's exact test was used, whereas non-normal distributed continuous variables were compared using Mann-Whitney-Wilcoxon test. Multivariable logistic regression models were developed to identify the potential factors associated with severe illness, calculation of odds ratios (ORs), and 95% confidence intervals. We first used a univariate regression model for candidate variable selection (P < 0.1), then performed a forward stepwise model selection based on Akaike's information criterion (AIC) and likelihood ratio test to select the explanatory variables in final model. Candidate variables are listed in the Supporting Information. A P value of <0.05 was considered statistically significant. All statistical analyses were performed in R v3.6.3 (R Foundation for Statistical Computing, Vienna, Austria).

| Characteristics of study population
Throughout the study years, a total of 7093 eligible ARI patients were admitted in the three wards. Out of these eligible patients, 5250 (74.0%) patients with an informed consent were enrolled in this study.
Remaining 1843 (26.0%) patients were excluded from the study on guardians' request. The main reason behind refusal of participation was the guardians' unwillingness for their children to receive the throat swab sampling procedure. Additional 11 patients were excluded due to incomplete medical records. In the end, 5239 patients remained in study for the screening of influenza and RSV infection.   As shown in Figure 2, the positivity rate of influenza increased with an increase in age of children, whereas it decreased for RSV with an increase in age. In 2020-2021, the RSV positivity rates remained high in majority of age groups, especially in the group of infants <4 months (P < 0.05) (Table S2) (Table S2). Influenza shared a similar epidemic season with RSV in 2018-2019. However, no usual peak was observed in the winter of 2020-2021.

| Characteristics of RSV and influenza inpatients
The age distribution for patients with RSV or influenza infection varied between these study years ( Table 1) (Table S3).

| Clinical course and disease severity
As shown in Table 2    17.4% (21/121) influenza-infected patients were treated with corticosteroids (P < 0.05) (    10,12 This altered activity patterns between these viruses hinted that the public health measures against SARS-CoV-2 had more effective impact on influenza than RSV. 5 One plausible reason for this observation could be the ability of RSV to survive for longer duration out of a host and its ability to quickly spread via direct contact. 9,21,22 Additionally, the children probably could not fully benefit from current preventive measures like wearing masks, particularly those under 1 year, toward whom face masks were not recommended. As compared to 2018-2019, a higher median age was observed in 2020-2021 in patients of ARI, RSV, and influenza (Table 1). During the pandemic, a similar older age structure of RSV and influenza patients was observed in the United States, France, and Australia. 5,19,20 One possible explanation for these comparatively older age structures could be the "immunity debt," resulting from the accumulation of immune-naïve children due to strict implementation of NPIs in the first half of 2020. Children in early life are most vulnerable to RSV, influenza, and other respiratory viruses had a lesser chance of natural exposure to infection. Thus, the infection rates did not increase until the lockdown was lifted and these children were a little older. 7,21 Besides, a higher proportion of eligible ARI patients in 2020-2021 from the age groups of >5 months old led to the enrollment of a little older children which could be another reason for older RSV-infected patients in our study (Table S1). Earlier studies showed, the young age of patients was associated with a higher positivity rate of RSV. 29 The finding that an older age structure of enrolled patients and a considerably higher rate of RSV positivity in 2020-2021 than 2018-2019 strengthened the conclusion that, RSV infections remained at a higher level during the COVID-19 pandemic.

| CONCLUSIONS
The NPIs during COVID-19 pandemic had varied impacts on common respiratory viruses. This was associated with a remarkably reduced incidence of influenza, while RSV infections remained at a higher level.
This observation highlighted the need to find a most effective preventive strategy for RSV infections in childhood.

ACKNOWLEDGEMENTS
We would like to thank all the patients for participating in our study, and we also thank Xinxing Ma and Dr. Shiyue Mei and the staff members at Henan Children's Hospital and Zhengzhou Central Hospital for helping with the field investigation, administration, and data collection.

CONFLICT OF INTEREST
HY has received research funding from Sanofi and Shanghai Roche Pharmaceutical Company. All other authors declare no competing interests.

ETHICS STATEMENT
The study was approved by School of Public Health, Fudan University

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.13103.

DATA AVAILABILITY STATEMENT
The data are not publicly available due to privacy or ethical restrictions. De-identified individual data that supports the findings of this study are available from the corresponding author on reasonable request. The data requestor will need to sign a data access agreement.